The present invention relates to the treatment of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) with or by activation of the hormone secretin or other secretin receptor ligands.
Cystic Fibrosis.
Cystic fibrosis (CF) is the most common, fatal, autosomal recessive inherited disease, with over 7000 people currently diagnosed in the UK alone and approximately 30,000 in the United States. The incidence of CF is strongly dependent on ethnic background. Caucasian individuals with Northern European ancestry are most at risk exhibiting a probability of approximately 1 in 2500, based on a heterozygous carrier rate of about 1 in 25.
CF arises as a result of genetic mutation(s) in the gene of the cystic fibrosis transmembrane regulator (CFTR) chloride channel throughout the body. Such mutations in the CFTR lead either to incorrect folding of the protein and/or the lack of migration of the transcribed protein from the Endoplasmic Reticulum to the epithelial plasma membrane and subsequent loss of chloride (Clxe2x80x94) channel function. This causes a cellular and luminal imbalance in fluid and electrolyte transport and volume within the lower respiratory tract of the CF lung, which reduces the constitution of the mucus which in turn impairs mucociliary clearance and initiates the inevitable and persistent bacterial infections within the lung of CF patients. Different mutations give rise to CF symptoms of varying severity and correspondingly lead to variations in patient survival rates.
Over the last few decades, improved drug and physiotherapy treatments have improved patient survival time significantly, though average life expectancy is still short, currently around 30 years. There is therefore a continuing need to develop better treatment for this condition.
COPD
Clinical features of COPD include breathlessness, cough and sputum, with chronic airway obstruction and lung hyperinflation as a result of chronic bronchitis and emphysema (dilation of the distal lung airspaces). Chronic bronchial hypereactivity which is prominent in bronchial asthma is also found in COPD. Airway remodelling in COPD leads to persistent and irreversible airway narrowing and mucus hypersecretion. The direct cause of airway narrowing and hyperresponsiveness is unknown although it is generally proposed that abnormalities in the airway smooth muscle function results in decreased or impaired relaxation or increased contractility.
A bronchodilator regimen combining a slow release oral theophylline with an inhaled beta 2 agonist (e.g. ipratropium, salbutamol, salmeterol), and high dose inhaled steroids represent current therapies utilised in the treatment of COPD, because even modest improvement in obstruction is beneficial in COPD patients. Beta 2 agonist mediate bronchodilation of the airways via the stimulation of specific receptors which are coupled to the specific G-protein G8, which in turn leads to an increase in the intracellular levels of the second messenger cAMP.
Recently Clxe2x88x92 ion movement has been demonstrated to be linked to epithelium-dependent airway relaxation (Fortner et al, 2001), such that blockade of Clxe2x88x92 ion secretion results in a significant reduction in agonist-induced relaxation. Additionally, compounds such as furosemide, a Clxe2x88x92 dependent Na+/K+/2Clxe2x88x92 co-transport inhibitor has been demonstrated, in some studies to decrease bronchial hyper-responsiveness in asthmatics (Pendino et al, 1998)). In addition, mucus hypersecretion and non-continuous clearance of tracheobronchial mucus also contribute to persistent airflow obstruction plugs, which can be present simultaneously with airway responsiveness. Mucus plugging can result in small airway (e.g. tertiary bronchus) obstruction producing reduced maximal respiratory flow and slow forced lung emptying.
Secretin
Secretin is a peptide hormone which is secreted from S cells in the proximal small intestine (especially the duodenum and jejunum) in response to acidic contents leaving the stomach. The structure of porcine secretin has been known for some time and it has been isolated from porcine intestine and has been found to be constituted by a peptide composed of 27 amino acid residues (Mutt et al, 1970). Moreover, it has been found that bovine and porcine secretins are identical, and are also similar to canine secretin.
Although bovine and porcine secreting behave identically with human secretin in some respects they are not structurally identical. These animal secretins differ from the human secretin at positions 15 and 16. An alignment of human, porcine and canine secretin is shown in FIG. 1.
Secretin""s physiological role is to stimulate water (H2O) and bicarbonate (HCO3xe2x88x92) secretion from the pancreas, leading to the neutralisation of acidic chyme. Its actions are mediated via a seven transmembrane domain, G protein coupled receptor (GPCR), a member of the glucagon-secretin-vasoactive intestinal peptide structurally related superfamily of GPCRs (IUPHAR Receptor Compendium, 1998), for which the peptide exhibits nanomolar affinity. Secretin receptor stimulation mediates increases in intracellular cAMP, and the activation of protein kinase A (PKA).
Secretin is currently approved by the FDA to diagnose gastrinoma and assess pancreatic function. Anecdotal reports from xe2x80x9coff-labelxe2x80x9d use of secretin in paediatric autism suggest that it may improve both physiological and behavioural symptoms associated with autism, a disorder characterized by severely impaired communication, social skills and development (see for example WO98/52593, U.S. Pat. No. 6,020,310 or U.S. Pat. No. 6,020,314). In Mar. 2000 Repligen Corporation (USA) announced it had initiated a Phase II clinical trial with secretin in children with autism, with the Phase II trial sites including the Mayo Clinic, the University of Rochester Medical Center and the Southwest Autism Research Center in collaboration with Phoenix Children""s Hospital. Initial results of these trials suggest that secretin infusion may be beneficial in discrete groups of severely autistic children.
Secretin has also been proposed for the prophylaxis of the aspiration pneumonia syndrome (e.g. in EP0150760; AU3806485).
There are a wide number of reported synthetic and/or naturally occurring secretin peptide analogues and fragments (referred to herein as xe2x80x9csecretin receptor ligandsxe2x80x9d) which exhibit a wide range of potencies, efficacies and selectivity for the secretin receptor. These include, but are not limited to mono/poly substituted secretin analogues, secretin fragments, substituted secretin fragments, reduced peptide bond analogues (Gardner et al, 1976; Gardner et al, 1979; Waelbroeck et al, 1981; Konig et al, 1984; Staun-Olsen et al, 1986; Robbertecht et al, 1988; Haffer et al, 1991), and naturally occurring and synthetic analogues, fragment and chimeric peptides of the VIP/secretin family (including VIP (vasoactive intestinal peptide), gastric inhibitory peptide (GIP), PACAP (pituitary adenylate cyclase-activating polypetide), adrenomedullin, calcitonin, CGRP (alpha, beta and skin calcitonin gene related peptides), glucagon, glucagon-like peptide (GLP), growth hormone-releasing factor, parathyroid hormone (PTH) and its related protein (PTHrP), corticotrophin-releasing hormone (CRH) and amylin Many of these peptides (including glucagon, GLP, PACAP and VIP share significant amino acid homology, particularly in the amino terminus with secretin. All these peptides are though to adopt similar secondary structural characteristics, including one or two regions of amphipathic xcex1-helical secondary structure, and appear to interact with their receptors in a well conserved manner (Sexton, 1999).
Also known are secretin-related receptor peptides, and associated analogues and fragments which exhibit affinity for the secretin receptor.
We have studied the expression levels of secretin receptor in tissue from patients with CF and COPD. We have found that in both normal individuals and patients with these disease conditions, secretin receptor is expressed in the distal regions of the lung, particularly the tertiary bronchus and parenchyma, with little or no measurable mRNA expression in more proximal regions of the lung. The expression of secretin receptor in these tissues has not previously been reported.
We have moreover surprisingly found that levels of secretin receptor mRNA in tertiary bronchus of CF patients are significantly elevated. This elevation is specific to CF, and not shared by patients with other lung disorders. The elevation was specific to tissue of the tertiary bronchus.
While not wishing to be bound by any one particular theory, we believe the action of secretin on ion movements in cells (see below) will counteract the effect of the CTFR deficiency associated with CF. Further, although the operation of the present invention does not rely upon any one particular theory, an explanation of the elevated levels of secretin receptor mRNA in tertiary bronchial tissue is that this is in response to the ion imbalance experienced in these cells.
Moreover, in patients with COPD there is increasing recognition that the role of ion efflux in the lungs of patients may be a critical target for therapeutic intervention. The secretin receptor is coupled to the G-protein, G8, and therefore it can be envisaged that activation of the functional secretin receptor that has been identified herein on epithelial cells lining the distal human bronchus will result in the accumulation of intracellular cAMP, and subsequent bronchodilation (see also Ng et al, 1999). Moreover in other mucus hypersecretory lung diseases, such as cystic fibrosis and COPD, reduction of predominantly Clxe2x88x92 efflux alters the aqueous and ionic composition and subsequent viscosity of mucus and mucus secretions, leading to thick insipid mucus which impairs mucociliary clearance from the lung. Thus the stimulation of ion movement in such patients may thus be beneficial in the treatment of their disease.
Accordingly, the present invention provides a method of treatment of cystic fibrosis in a patient suffering from CF, the method comprising administering to said patient an effective amount of an agent which triggers anion efflux in respiratory tissue via the activation of a secretin receptor.
The invention further provides a method of treatment of COPD in a patient suffering from COPD, the method comprising administering to said patient an effective amount of an agent which triggers anion efflux in respiratory tissue via the activation of a secretin receptor.
The present invention is in one part based on the surprising finding by the inventors of elevated levels of secretin receptor mRNA in the tertiary bronchus of CF patients, and relates to the novel use of secretin in the treatment of cystic fibrosis. A preferred aspect of the invention is directed to the treatment of CF by the administration to the patient of a secretin receptor ligand. However, it has been contemplated by the inventors that secretin may be delivered to the patient in an effective amount by means other than directly administering the secretin receptor ligand itself. An alternative method of administering secretin is by the use of agents which stimulate the up-regulation of the production and or release of endogenous secretin in pulmonary cells, or secretin related peptides.
The invention also provides the use of an agent which triggers anion efflux in respiratory tissue via the activation of a secretin receptor for the manufacture of a medicament for the treatment of cystic fibrosis.
The invention additionally provides the use of an agent which triggers anion efflux in respiratory tissue via the activation of a secretin receptor for the manufacture of a medicament for the treatment of COPD.
Preferably, the agent is a secretin receptor ligand, more particularly secretin, particularly human secretin.